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研究生:鍾葦璇
研究生(外文):Chung, Wei-Hsuan
論文名稱:絲氨酸合成與單碳代謝路徑在自體免疫T細胞的角色
論文名稱(外文):The role of serine synthesis pathway and one-carbon metabolism in autoimmune T cell
指導教授:呂春敏
指導教授(外文):Leu, Chuen-Miin
口試委員:陳念榮繆希椿
口試委員(外文):Chen, Nien-JungMiaw, Shi-Chuen
口試日期:2023-07-27
學位類別:碩士
校院名稱:國立陽明交通大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
語文別:中文
論文頁數:49
中文關鍵詞:絲氨酸合成路徑單碳循環代謝自體免疫T細胞增殖
外文關鍵詞:serine synthesis pathwayone carbon metabolismautoimmuneT cell proliferation
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在受到病原刺激後,T細胞會透過活化、增殖,接著分化成不同種類的effector T細胞,來清除病原體。在活化的過程中,T細胞會改變自身的代謝來滿足活化所需要的能量。舉例來說,需要提升葡萄糖及氨基酸的攝取及代謝,這個現象就稱為代謝重組。近期的研究發現,絲氨酸合成與單碳代謝路徑,合稱絲氨酸、甘氨酸與單碳代謝對於T細胞具有重要性,這兩條代謝途徑會影響T細胞的增殖與細胞激素分泌。然而,這兩條代謝途徑對於自體免疫T細胞的作用尚不清楚。本論文目標在了解絲氨酸、甘氨酸與單碳代謝路徑對於自體免疫T細胞的影響。實驗結果顯示,絲氨酸合成基因PHGDH和PSAT1在類風濕性關節炎T細胞中表現量較健康T細胞低。而紅斑性狼瘡B細胞中則是單碳代謝路徑中的MTHFD2表現量較高,其餘的基因與健康受試者相比則沒有顯著的差別。然而,在類風濕性關節炎與紅斑性狼瘡患者B細胞中發現,MTHFD2區分為表現量高及表現量低的兩群。當使用PHGDH、SHMT或MTHFD2抑制劑,針對T細胞增殖測量結果發現,單一抑制劑皆可以抑制自體免疫CD4+及CD8+ T細胞的細胞增殖。此外,初步的結果發現,PHGDH 和MTHFD2抑制劑均能降低T細胞活化後IFNγ和IL-17F的表現,同時PHGDH抑制劑可能對於FOXP3的表現量有抑制作用。總結我們的實驗結果,類風濕性關節炎T細胞中PHGDH和PSAT1表現量下降,紅斑性狼瘡B細胞MTHFD2表現量上升。針對T細胞,兩條代謝途徑的抑制劑皆可以抑制細胞增殖。所以我們認為絲氨酸、甘氨酸與單碳代謝路徑可以作為類風濕性關節炎及紅斑性狼瘡治療的新標的。
After stimulation, T cells undergo activation, proliferation, and differentiation to effector cells to carry out their functions. During activation, T cells reprogram their metabolism to meet their demands. For instance, the uptake and metabolism of glucose and amino acids will be increased. Recent studies have revealed that the serine synthesis pathway (SSP) and one-carbon (1C) metabolism also play an important role in T cells. Previous results indicate that serine or 1C metabolism is required for T cell proliferation and cytokine production. However, the role of these two metabolic pathways in autoimmune disease is still unclear. We aimed to study whether the serine, glycine, and one-carbon (SGOC) metabolism affects the functions of T cells in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). First, we sorted T cells and B cells from patients and healthy donors and measured the expression of SGOC genees by RT-qPCR. We found that the expression of the SSP genes, PHGDH and PSAT1, was lower in the T cells from RA patients. Moreover, the expression of 1C gene MTHFD2 was higher in the B cells from SLE patients. The expression of the other SGOC genes in lymphocytes from RA or SLE was not different from that in healthy donors. We found that the expression of MTHFD2 in RA or SLE patients could be divided into two groups — high expression and low expression. Whether MTHFD2 expression is associated with disease activity remains to be tested. Treating with PHGDH, SHMT, or MTHFD2 inhibitors markedly inhibited cell proliferation both in CD4+ and CD8+ T cells. Our preliminary results showed that the expression of IFNγ and IL-17F in activated T cells was suppressed by PHGDH or MTHFD2 inhibitor. The expression of FOXP3 was inhibited by PHGDH inhibitor. In summary, we found that the expression of SGOC genes were comparable in T cells or B cells from patients with RA and SLE, except MTHFD2. However, T cell proliferation was decreased by either SSP or 1C inhibitor. Therefore, SGOC genes may be a new therapeutic target for patients with RA and SLE.
摘要 i
Abstract ii
目錄 iv
圖表目錄 v
第一章 緒論 1
1.1 T細胞活化與代謝重組 1
1.2 絲氨酸、甘氨酸與單碳代謝 (serine, glycine and one-carbon metabolism, SGOC metabolism) 1
1.3 絲氨酸、甘氨酸與單碳代謝的基因調控 2
1.4 SGOC代謝在免疫細胞中的功能 3
1.5 自體免疫疾病—類風濕性關節炎及紅斑性狼瘡其中T細胞的代謝變化 4
1.6 自體免疫疾病與絲氨酸、甘氨酸與單碳代謝 5
1.7 研究動機 5
第二章 材料與方法 6
2.1 材料 6
2.2 方法 11
第三章 實驗結果 15
第四章 討論 22
參考資料 26
圖表 31
附錄 48
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